Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

睡眠呼吸暂停不良健康结果的表型机制途径

• 批准号: 10687050
• 负责人: Ali Azarbarzin
• 金额: $ 66.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687050
• 关键词: Acute; Adherence; Adverse event; Affect; Apnea; Arousal; Attention; Biological Markers; Blood Pressure; Blood gas; Cardiovascular Diseases; Cardiovascular system; Caring; Clinical Trials; Confusion; Continuous Positive Airway Pressure; Data; Diagnosis; Disease; Drowsiness; Endothelium; Event; Excessive Daytime Sleepiness; Exhibits; Failure; Goals; Grant; Health; Health Benefit; Heart Rate; Heart failure; Hour; Hypoxemia; Hypoxia; Individual; Knowledge; Link; Measures; Mediating; Methods; Monitor; Neurocognitive; Neurocognitive Deficit; Nitrates; Nitric Oxide; Nitrites; Observational Study; Obstructive Sleep Apnea; Outcome; Outcome Assessment; Oxidative Stress; Pathogenicity; Pathway interactions; Patient Selection; Patient-Focused Outcomes; Patients; Performance; Persons; Pharyngeal structure; Phenotype; Physiological; Plasma; Prognostic Marker; Quality of life; Research; Risk; Severities; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Splint Device; Sympathetic Nervous System; Telephone; Testing; Therapeutic; Time; Vasodilation; Visit; Woman; Work; adverse outcome; airway obstruction; automobile accident; biomarker identification; cardiometabolism; effective therapy; follow-up; high risk; high risk population; improved; indexing; individualized medicine; men; mortality; novel; patient subsets; personalized medicine; prevent; response; vigilance

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder with adverse neurocognitive and cardio-metabolic outcomes. Continuous positive airway pressure (CPAP) is the gold standard therapeutic option to treat airway obstructions during sleep and thus, prevent its adverse cardiovascular and neurocognitive outcomes. Previous clinical trials, however, have largely failed to show a consistent impact of CPAP on these health outcomes. One of the main limitations of these trials is, we believe, inadequate characterization of OSA and its acute physiological consequences. By characterizing OSA based on the “apnea-hypopnea index (AHI)”, there is a potential risk of negative results. We surmise that, by better characterization of OSA-related physiological consequences during sleep, we will be able to identify individuals at high risk for these adverse outcomes and those who would benefit most from therapy. We have developed physiologically driven metrics to capture the precise burden of OSA-related hypoxemia (“hypoxic burden”), autonomic response (“heart rate burden”), and sleep fragmentation (“arousal burden”). Our preliminary data from large observational studies suggest that these metrics outperform conventional sleep study parameters. In Aim 1, we seek to demonstrate that OSA patients with high hypoxic burden will exhibit greater improvements, after 12 weeks of CPAP therapy, in endothelial function (flow-mediated vasodilation) and oxidative stress markers than those with a low hypoxic burden. In Aim 2, we will investigate how heart rate burden determines the reduction in 24-hour mean blood pressure after 12 weeks of CPAP treatment. Finally, in Aim 3, we will seek to demonstrate that OSA patients with larger degrees of sleep fragmentation, quantified by arousal burden, will respond more favorably to CPAP, in terms of improvement in daytime sleepiness and attention, than those with low arousal burden. While the primary analysis will be the change in these outcomes after 12 weeks of CPAP, we will also assess these outcomes at 4 weeks to examine their time course. A total of 158 men and women with apnea-hypopnea index ≥15 events/hour will receive CPAP for 12 weeks. Adherence to therapy will be carefully monitored and encouraged by regular phone calls and in-person visits. Adverse events will also be closely monitored and recorded. Overall, our proposal is expected to demonstrate that prognostic markers of OSA that more strongly link with health outcomes will not only improve the diagnosis of OSA, but also provide a physiological basis for identifying those individuals most responsive to CPAP therapy. These results will have key mechanistic implications for “individualized medicine” in OSA by focusing on subgroups of patients who would most benefit from CPAP therapy. This personalized medicine approach will provide the scientific knowledge needed to progress towards larger studies in selected patients. Such results are of major importance because they have great potential to improve the quality of life and health outcomes of patients with OSA.

项目总结/文摘

项目成果

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

阻塞性睡眠呼吸暂停中驱动力与压力对颏舌肌活动的影响。

• DOI: 10.1513/annalsats.202301-083oc
• 发表时间: 2023
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Gell,LauraK;Vena,Daniel;Grace,Kevin;Azarbarzin,Ali;Messineo,Ludovico;Hess,LaurenB;Calianese,Nicole;Labarca,Gonzalo;Taranto-Montemurro,Luigi;White,DavidP;Wellman,Andrew;Sands,ScottA
• 通讯作者: Sands,ScottA

Screening for Obstructive Sleep Apnea in Adults.

成人阻塞性睡眠呼吸暂停筛查。

• DOI: 10.1001/jama.2022.20670
• 发表时间: 2022
• 期刊: JAMA
• 作者: Gottlieb,DanielJ

Loop Gain as a Predictor of Blood Pressure Response in Patients Treated for Obstructive Sleep Apnea: Secondary Analysis of a Clinical Trial.

循环增益作为阻塞性睡眠呼吸暂停治疗患者血压反应的预测因子：临床试验的二次分析。

• DOI: 10.1513/annalsats.202305-437oc
• 发表时间: 2024
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Schmickl,ChristopherN;Orr,JeremyE;Sands,ScottA;Alex,RaichelM;Azarbarzin,Ali;McGinnis,Lana;White,Stephanie;Mazzotti,DiegoR;Nokes,Brandon;Owens,RobertL;Gottlieb,DanielJ;Malhotra,Atul
• 通讯作者: Malhotra,Atul

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility.

• DOI: 10.1111/resp.14326
• 发表时间: 2022-11
• 期刊: RESPIROLOGY
• 影响因子: 6.9
• 作者: Messineo, Ludovico;Taranto-Montemurro, Luigi;Calianese, Nicole;Gell, Laura K.;Azarbarzin, Ali;Labarca, Gonzalo;Vena, Dan;Yang, Hyung Chae;Wang, Tsai-Yu;Wellman, Andrew;Sands, Scott A.
• 通讯作者: Sands, Scott A.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

• DOI: 10.1183/13993003.00828-2023
• 发表时间: 2023-12
• 期刊: The European respiratory journal